Oxidation inhibitors in prostane derivatives

ABSTRACT

The invention relates to the use of an oxidation inhibitor, i.e. active carbon, for ambient air in industrial manufacturing, especially in the processing of prostane derivatives, whereby the oxidation inhibitor removes ozone from the process air before contact with said prostane derivatives. The concentration of decomposition products is reduced.

The invention relates to the use of an oxidation inhibitor for theambient air in industrial manufacturing, especially in the processing ofprostane derivatives, in this case preferably during the wet phase.

PRIOR ART

The active ingredient “iloprost-β-cyclodextrin” bears the systematicdesignation5-(E)-(1S,5S,6R)-7-hydroxy-6[(E)-(3S,4RS)-3-hydroxy-4-methyl-1-octen-6-inyl]bicyclo[3.3.0]-octen-3-ylidenepentanoic acid as a β-cyclodextrin inclusion compound. The activeingredient is manufactured in the form of crude pellets by the followingsteps.

(i) Mixing of the active ingredient iloprost-β-cyclodextrin and theadjuvants lactose and avicel,

(ii) Pelletization with about 20.5% water,

high-speed mixing,

extruding and

spheronization,

(iii) Drying in a fluidized-bed dryer,

filling and

drying.

The individual steps are described in detail in the followingliterature: H. SUCKER, P. FUCHS, and P. SPEISER: PharmazeutischeTechnologie [Pharmaceutical Technology], Georg Thieme Verlag, Stuttgart,N.Y., 2nd Edition, 1991.

It should be noted that the pelletization in step (ii) is carried outintermittently, i.e., the active-ingredient-containing powder mixturewith 0.1% iloprost is processed in cycles in about 5 kg portions. Themoist crude pellet cycles are first collected in succession in afluidized-bed dryer. After the last cycle in the dryer takes place, thefinal drying begins.

In the above-mentioned production process, methane-diol-ketonecontamination occasionally occurred in addition to the pure iloprost.This corresponds to the nomenclature with the name(1S,2R,3R,5R)-3-hydroxy-2-[(E)-(3S,4RS)-3-hydroxy-4-methyl-1-octen-6-inyl-bicyclo[3.3.0]octan-7-one.In this case, this is a decomposition product that is produced byoxidation. In the case of an occurrence, various parameters wereimportant for the amount of decomposition product. In the wet state, theoxidation depended on the water content and the incubation time. It wasseen that the temperature can play a role. It was also obvious that theactive ingredient was sensitive to the mixture with avicel and lactose,but not to the active ingredient by itself. Although the same parameterswere maintained, different amounts of decomposition product, whichoccasionally was allowed below the detection limit of <0.1%, wereproduced. Thus, occasionally values of between 0.6% to 4% were used. Asa result, the purity requirements were not always met.

OBJECT AND ACHIEVEMENT

The object is thus to offer oxidation protection in the production,especially in the processing of prostane derivatives, whereby theoxidation products are avoided or are considerably reduced in theirconcentration.

The object is achieved by using an oxidation inhibitor for the ambientair in the case of industrial manufacturing, especially in theprocessing of prostane derivatives, whereby the oxidation inhibitorremoves ozone from the process air before making contact with theprostane derivatives.

Oxidation Inhibitors

The oxidation inhibitor can be

an inert gas atmosphere,

a closed circuit that consists of synthetic air,

a metal catalyst,

an irradiation device with ultraviolet light,

a heating: device with temperatures of at least 250° C. and a coolingdevice of the process air, or

an activated-carbon filter, through which the process air flows.

Combinations that consist of oxidation inhibitors are also possible.

The oxidation inhibitors are characterized as follows:

An inert gas atmosphere can consist of a nitrogen atmosphere or else anoble gas.

Synthetic air is run as a circuit, whereby the water that accumulatesduring drying must be removed. In this case, the composition of theprocess air can essentially correspond to the atmospheric air with theexception of ozone.

Platinum, copper or magnesium oxide may be metal catalysts.

Irradiation with ultraviolet light is preferably carried out at 254 nm.

The process air is heated preferably to 300° C. in the heating device.In this case, this air must then again be cooled in the cooling device.Both processes are preferably carried out in a heat exchanger.

Advantages

The different amounts of decomposition product with otherwise identicalparameters were randomly determined as a function of the ozone contentin the outside air. In this case, it can be noted that a monitoring ofthe ozone concentration in the pharmaceutical range is uncommon. Suchmonitoring has still not been described. A complicating factor is thefact that the decomposition products only occur if a threshold value ofabout 20 μg of ozone/m³ of ambient air is exceeded in the production.Consequently, no clear connection between the ozone concentration andthe outside air was to be seen, so that a technical solution, which cansuppress the decomposition products satisfactorily, was unlikely.

State of the Prostane Derivatives

Use of an oxidation inhibitor is preferred, whereby the prostanederivatives are mixed with cyclodextrin.

It has been shown that the oxidation occurs to an increased extent ifthe prostane derivatives are mixed with cyclodextrin. It is known,however, that specifically the complexes that consist of prostanederivatives and cyclodextrin are especially stable relative to anoxidation. Here, an otherwise common principle is thus violated.

The use of an oxidation inhibitor is preferred, whereby the prostanederivatives are found in a wet phase.

The presence of water results in an increased oxidation. Specifically inthis case, oxidation proceeds more vigorously. As a result, the handlingof the entire process is made more difficult, however. The moisture inthe prostane derivatives and preferably in the complexes that consist ofprostane derivatives and cyclodextrin must be removed. In this respect,cold traps or other devices are necessary to remove the water vapor fromthe process air.

Preferred is an activated-carbon filter with the following properties:(i) short contact times, (ii) minimum possible pressure drop through thefilter, (iii) activated carbon has hydrophobic properties, and (iv) thefilters have long service lives.

Prostane Derivatives

Preferred are prostane derivatives of general formula I or formula II

in which

X₁ is a —CH₂—CH₂—; trans —CH═CH— or —C≡C—,

X₂ is a straight-chain or branched, saturated alkylene group with 1 to 6carbon atoms,

X₃ is an —O— or —CH₂—,

X₄ is a —CH₂— or —[CH₂]₃—,

X₅ is an —H or —C≡C—R₂,

R₁ is a hydrogen atom, an alkyl group with 1 to 6 carbon atoms, acycloalkyl group with 5 or 6 carbon atoms or phenyl group,

R₂ is a straight-chain or branched-chain, saturated or unsaturated alkylgroup with 1 to 6 carbon atoms,

R₃ is a hydrogen atom, an acyl radical with 1 to 4 carbon atoms or abenzoyl radical, and

R₄ is an —H or —CH₃;

whereby the —O—R₃ group is in α- or β-position, and their salts withphysiologically compatible bases, if R₁ has the meaning of a hydrogenatom.

X₂ stands for straight-chain or branched, saturated alkylene groups with1 to 6 carbon atoms, thus, for example, methylene, ethylene, propylene,isopropylene, whereby the methyl group is connected to the first orsecond carbon atom of ethylene, calculated from group A; butylene,methylpropylene, ethylethylene, dimethylethylene, whereby the methyl orethyl group is connected arbitrarily to the alkylene chain; pentyl,methylbutylene, dimethylpropylene, ethylpropylene, methylethylethylene,whereby the methyl or ethyl groups are connected arbitrarily to thealkylene chain; hexylene, methylpentylene, dimethylbutylene,methylethylpropylene, whereby the methyl or ethyl group is connectedarbitrarily to the alkylene chain.

Alkyl group R₁ comprises straight or branched alkyl groups with 1 to 6carbon atoms, such as, for example, methyl, ethyl, propyl, butyl,isobutyl, tert-butyl, pentyl, neopentyl or hexyl.

Cycloalkyl group R₁ can contain 5 or 6 carbon atoms in the ring.

Alkyl group R₂ can consist of straight-chain or branched-chain,saturated or unsaturated alkyl radicals with 1 to 6 carbon atoms, andthe alkyl radicals are preferably saturated. For example, methyl, ethyl,propyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, butenyl, isobutenyl,propenyl, pentenyl or hexenyl groups can be mentioned.

Acyl group R₃ can consist of a straight-chain or branched-chain acylgroup with 1 to 4 carbon atoms, such as, for example, acetyl, propionyl,butyryl or isobutyryl.

For salt formation with the free acids, inorganic and organic bases aresuitable, as they are known to one skilled in the art for the formationof physiologically compatible salts. For example, there can bementioned: alkali hydroxides, such as sodium and potassium hydroxide,alkaline-earth hydroxides, such as calcium hydroxide, ammonia, amines,such as ethanolamine, diethanolamine, triethanolamine,N-methylglucamine, morpholine, tris-(hydroxymethyl)-methylamine, etc.The β-cyclodextrin clathrate formation is carried out according to EP 0259 468.

The prostane derivative5-(E)-(1S,5S,6R)-7-hydroxy-6[(E)-(3S,4RS)-3-hydroxy-4-methyl-1-octen-6-inyl]bicyclo[3.3.0]octen-3-ylidenepentanoic acid is preferred. Most preferred is the above-mentionedcompound as a β-cyclodextrin inclusion compound.

Preferred is the use up to an ozone concentration of 20 μg/m³ in theambient air during production. The outside air is not decisive byitself. During the suctioning of air from the outside air, ozone iscatabolized, which is carried out solely by making contact with solidobjects.

Advantages of the Activated-Carbon Filter

It was not logical and obvious to select activated carbon as oxidationprotection, as the otherwise not so successful attempts to reduce theozone content showed.

As a first solution, a nitrogen atmosphere was proposed, which, however,for technical reasons still contains residual amounts of oxygen, i.e.,also ozone with respect to portions. The solution was not satisfactory.Further removal of oxygen would have been very costly in this situation.Moreover, the nitrogen atmosphere can only reasonably be implemented inan ambient air operation. In this case, because of the recycling of theair, an increased risk of cross-contamination exists.

As a second solution, it was proposed to operate the unit by itself withsynthetic air in a circuit. In this case, the solution would also bevery costly. As already depicted above, in this case the danger existsthat a cross-contamination would occur.

As a third solution, metal catalysts that consist of platinum, copper ormanganese oxide were used. The experts have given advice to this effect.The ozone reduction was not satisfactory, however. Also, in this case, acostly solution would have had to be adopted. Moreover, the use ofsupplied metal catalysts is connected to a high pressure loss. This hasa negative effect on the filling of the dryer owing to the displacementof the pressure potential in the unit.

As a fourth solution, an irradiation with ultraviolet light wasproposed. In this case, the danger exists that additional oxygenradicals are produced, which then must also be removed. This solutionalso turned out to be uneconomical.

In a fifth solution, air was heated to 300° C. In this case, ozone isthermally decomposed. It is unfavorable that the air must be cooledagain to have a temperature of about 40° C. and less. It isdisadvantageous that in the ventilation center, the necessary spacerequired for the assemblies is not available.

The preferred solution with activated-carbon filters was not obvious,since the experts advised against using activated carbon, since thepressure drop through the activated-carbon filter was estimated as beingtoo high. In this case, it is important to indicate that the air issuctioned, not pressed through the fluidized-bed dryer. The ventilatoror the turbine is thus ruled out as a contamination source. In addition,these filters tend toward the abrasion of carbon particles that can getinto the product bed. In addition, it must be calculated over longerservice lives by the entering wet outside air with microbialcontamination.

Nevertheless, this solution represents the best operating solution.

Process for the Production of Prostane Derivatives

In addition, the invention comprises a process for the production,especially processing, of medications that contain prostane derivatives,with use according to the invention of an oxidation inhibitor,comprising the following steps:

(i) Mixing of the active ingredient prostane-derivative-cyclodextrin andthe adjuvants lactose and avicel,

(ii) Pelletization with water, preferably with 15 to 25% water, morepreferably with 20-21% water,

high-speed mixing,

extruding and

spheronization,

(iii) Drying in a fluidized-bed dryer,

filling and

drying.

Preferred is a process for the production of medications that containprostane derivatives with use according to the invention of an oxidationinhibitor, comprising the following steps:

(i) Mixing of the active ingredient iloprost-β-cyclodextrin, which bearsthe systematic designation5-(E)-(1S,5S,6R)-7-hydroxy-6[(E)-(3S,4RS)-3-hydroxy-4-methyl-1-octen-6-inyl]bicyclo[3.3.0]octen-3-ylidenepentanoic acid, and the adjuvants lactose and avicel,

(ii) Pelletization with water, preferably with 15 to 25% water, morepreferably with 20-21% water,

high-speed mixing,

extruding and

spheronization,

(iii) Drying in a fluidized-bed dryer,

filling and

drying.

EXAMPLE

The superiority of the invention is confirmed by examples. In this case,test preparations are implemented with and without activated-carbonfilters. To test the action of the technical solution, a process airwith an ozone content of 350±25 μg/m³ is produced artificially, which,on the one hand, reaches the active ingredient directly, and, on theother hand, moves along the passage through an activated-carbon filter.In this case, an amount of air of 0.8 m³/sec is conveyed through thefilter.

If no filter is used, the process air in the contact area with theactive ingredient has a content of 350±25 μg of ozone/m³ of air. In thiscase, 5% decomposition products (w/w) are produced.

If an activated-carbon filter with the following properties is used, theozone content is reduced to 8±0.5 μg of ozone/m³ of air in the contactarea with the active ingredient. Properties of the activated-carbonfilter: (i) short contact times, (ii) minimum possible pressure dropthrough the filter, (iii) activated carbon has hydrophobic properties,and (iv) the filters have long service lives.

The filter is a standard activated-carbon filter, pressed fromcylindrical shaped bodies with a diameter of about 3 mm, which are usedas filter cartridges. As a result, 0.1% and less decomposition products(w/w) are produced. Such an amount of decomposition products ispharmacologically harmless.

At this time according to this process, the active ingredient5-(E)-(1S,5S,6R)-7-hydroxy-6[(E)-(3S,4RS)-3-hydroxy-4-methyl-1-octen-6-inyl]bicyclo[3.3.0]octen-3-ylidenepentanoic acid is produced as a β-cyclodextrin inclusion compound.

What is claimed is:
 1. A process comprising providing an oxidationinhibitor to provide a reduced ozone content process gas beforecontacting the gas with an active ingredient.
 2. A process according toclaim 1, wherein the oxidation inhibitor is an inert gas atmosphere, aclosed circuit comprising synthetic air, a metal catalyst, anirradiation device with ultraviolet light, a heating device withtemperatures of 250° C. and more and a cooling device of the processgas, and an activated-carbon filter, through which the process gasflows.
 3. A process according claim 2, wherein the activated-carbonfilter has: (i) a short contact time, (ii) a minimum possible pressuredrop through the filter, (iii) a hydrophobic activated carbon, and (iv)a long service life filter.
 4. A process according to claim 1, whereinthe active ingredient is a prostane derivative.
 5. A process accordingto claim 4, wherein the prostane derivative is found in a wet phase. 6.A process according to claim 3, wherein the prostane derivative is5-(E)-(1S,5S,6R)-7-hydroxy-6[(E)-(3S,4RS)-3-hydroxy-4-methyl-1-octen-6-inyl]bicyclo[3.3.0]octen-3-ylidenepentanoic acid.
 7. A process according to claim 6, wherein the prostanederivative is a β-cyclodextrin inclusion compound.
 8. A processaccording to claim 1, wherein the oxidation inhibitor is an inert gasatmosphere, a closed circuit comprising synthetic air, a heating devicewith temperatures of at least 250° C. and a cooling device, or anactivated carbon filter.
 9. A process according to claim 1, wherein theoxidation inhibitor is an activated carbon filter.
 10. A processaccording to claim 1, wherein the active ingredient comprises a mixtureof a prostane derivative and a cyclodextrin.
 11. A process according toclaim 1, wherein the process gas is air.
 12. A process according toclaim 11, wherein the reduced ozone content of the process gas is nomore than 20 μg of ozone/m³ of air.
 13. A process for producing amedication comprising a prostane derivative comprising: (i) mixing ofthe active ingredient prostane-derivative-cyclodextrin and the adjuvantslactose and avicel in the presence of a process gas with a reduced ozonecontent, (ii) pelletizing with about 20.5% water high-speed mixingextruding spheronization (iii) drying in a fluidized-bed dryer fillingdrying.
 14. A process for producing a medication comprising a prostanederivative, comprising: (i) mixing of the active ingredientiloprost-β-cyclodextrin, which bears the systematic designation5-(E)-(1S,5S,6R)-7-hydroxy-6[(E)-(3S,4RS)-3-hydroxy-4-methyl-1-octen-6-inyl]bicyclo[3.3.0]octen-3-ylidenepentanoic acid, and the adjuvants lactose and avicel in the presence ofa process gas with a reduced ozone content, (ii) pelletizing with about20.5% water high-speed mixing extruding spheronization (iii) drying in afluidized-bed dryer filling drying.
 15. A process for making a medicantcomprising reducing the ozone content in air by treating the air with anoxidation inhibitor.
 16. A process according to claim 15, wherein theoxidation inhibitor is a metal catalyst, an ultraviolet lightirradiation device, a heat device of at least 250° C. and a coolingdevice, or an activated-carbon filter.
 17. A process according to claim15, wherein the oxidation inhibitor is an activated-carbon filter.
 18. Aprocess according to claim 15, wherein the reduced ozone content of theair is no more than 20 μg of ozone/m³ of air.
 19. A process according toclaim 15, further comprising processing an active ingredient in thepresence of a reduced ozone content air.
 20. A process according toclaim 19, wherein the active ingredient comprises a cyclodextrin.
 21. Aprocess according to claim 19, wherein the active ingredient comprises aprostane derivative.
 22. A process according to claim 19, wherein theprostane derivative is of the formula:

wherein: X₁ is a —CH₂—CH₂—; trans —CH═CH— or —C≡C—, X₂ is astraight-chain or branched, saturated alkylene group with 1-6 carbonatoms, X₃ is an —O— or —CH₂—, X₄ is a —CH₂— or —[CH₂]₃—, X₅ is an —H or—C≡C—R₂, R₁ is a hydrogen atom, an alkyl group with 1-6 carbon atoms, acycloalkyl group with 5 or 6 carbon atoms or a phenyl group, R₂ is astraight-chain or branched-chain, saturated or unsaturated alkyl groupwith 1-6 carbon atoms, R₃ is a hydrogen atom, an acyl radical with 1-4carbon atoms or a benzoyl radical, and R₄ is an —H or —CH₃; wherein the—O—R₃ group is in α- or β-position, and its salts with physiologicallycompatible bases, if R₁ has the meaning of a hydrogen atom.
 23. Aprocess according to claim 22, wherein X₂ is methylene, ethylene,propylene, isopropylene, butylene, methylpropylene, ethylethylene,dimethylethylene, pentyl, methylbutylene, dimethylpropylene,ethylpropylene, methylethylethylene, hexylene, methylpentylene,dimethylbutylene, or methylethylpropylene.
 24. A process according toclaim 22, wherein R¹ is methyl, ethyl, propyl, butyl, isobutyl,tert-butyl, pentyl, neopentyl or hexyl.
 25. A process according to claim22, wherein R² is methyl, ethyl, propyl, butyl, isobutyl, tert-butyl,pentyl, hexyl, butenyl, isobutenyl, propenyl, pentenyl or hexenyl.
 26. Aprocess according to claim 22, wherein R³ is acetyl, propionyl, butyrylor isobutyryl.
 27. A process for making a medicant comprising processingan active ingredient in a reduced ozone atmosphere.
 28. A processaccording to claim 27, wherein the reduced ozone atmosphere is an inertgas atmosphere.
 29. A process for a prostane derivative, comprisingproviding a process gas with a reduced ozone content by a means foroxidation inhibition.